Molecular basis of activation of the orphan nuclear receptor Nurr1

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Small molecule ligands that activate the orphan nuclear receptor Nurr1 (NR4A2) hold promise as neuroprotective therapeutic agents or adjuvants to aging-associated neurodegenerative and dementia disorders characterized by a loss of neuron function including Parkinson's disease (PD) and Alzheimer's disease (AD). Nurr1 activating ligands show functional efficacy in animal models of AD and PD. However, although nuclear receptors are considered to be ligand-dependent transcription factors, Nurr1 is thought to function independent of binding an endogenous ligand that is produced and present in cells. Several synthetic ligands that activate Nurr1 transcription have been reported, but most have not been validated to directly bind Nurr1 and their mechanism of action remains unknown, which has stunted efforts to optimize Nurr1 ligands for AD and PD. Furthermore, Nurr1 regulates transcription as a monomer and as a Nurr1-RXR heterodimer. Synthetic RXR ligands that activate transcription of Nurr1-RXR heterodimers also display functional efficacy in animal models of AD and PD. However, it remains poorly understood how RXR and RXR-binding ligands impact the function of Nurr1-RXR on the structural level. In this project, we will address these knowledge gaps using mechanistic studies to define how small molecule ligands impact Nurr1 and Nurr1-RXR activation on the molecular, structural, and cellular levels using NMR spectroscopy, X-ray crystallography, mass spectrometry coupled to hydrogen/deuterium exchange (HDX-MS) and chemical crosslinking (XL-MS) and small angle X-ray scattering along with biochemical and cellular functional assays. These data will inform the design of new and improved Nurr1 activating ligands to determine if direct targeting of Nurr1 or indirect targeting via RXR is a viable option for AD and PD treatment